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Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma

Published:October 18, 2021DOI:https://doi.org/10.1016/j.jaci.2021.10.003

      Background

      Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described.

      Objective

      We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease.

      Methods

      We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain–containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet–induced obesity and asthma.

      Results

      Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet–induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet–induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma.

      Conclusion

      We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine–targeted biologics and inflammasome inhibitors.

      Key words

      Abbreviations used:

      AHR (Airway hyperresponsiveness), α-IL-5 or -13 (Anti–(α)-IL-5 or -13), BALF (Bronchoalveolar lavage fluid), BMI (Body mass index), CC (Control chow), CCR3 (C-C motif chemokine receptor type 3), DEX (Dexamethasone), HFD (High-fat diet), Iso (Isotype), NLR (NOD-like receptor), NLRP (NLR family, pyrin domain containing), NOD (Nucleotide-binding oligomerization domain), Ova (Ovalbumin), Sal (Saline), T2 (Type 2)
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